This research studies the component-specific molecular biophysics and physiological activity of biological and synthetic pulmonary surfactants. A major goal is to develop new highly active phospholipase-resistant synthetic exogenous surfactants containing novel lipids and peptides for use in the neonatal and acute respiratory distress syndromes (RDS and ARDS). The research also seeks to improve fundamental understanding about surfactant activity and dysfunction. Aims 1 and 2 examine the surface activity, resistance to inhibition, and P-V mechanical effects in lavaged excised rat lungs of synthetic exogenous surfactants containing novel phospholipase-resistant phospholipid analogs plus synthetic peptides or purified apoproteins. Lavaged calf lung surfactant and current animal-derived clinical surfactants are comparative standards. Complementary biophysical methods are used to fully assess surface-active behavior (Wilhelmy balance, pulsating bubble, adsorption, Brewster-angle microscopy, differential scanning calorimetry, FTIR spectroscopy). Materials studied include synthetic di-ether and ether-thio-phosphonolipids and phospholipids, synthetic regional human-sequence SP-B, SP-C, and SP-A peptides, synthetic glycerophospholipids, and specific lipids and apoproteins purified chromatographically from natural surfactant. Biophysical and excised lung studies in Aims 1, 2 are extended in Aim 3, to define the efficacy of the most active exogenous surfactants in reversing surfactant dysfunction, improving gas exchange, and reducing lung injury in rats with ARDS-related gram negative pneumonitis in vivo. Also studied is the formulation of surfactant dispersions with low shear viscosity to enhance their pulmonary delivery and distribution following tracheal instillation. This integrated hierarchy of biophysical and physiological research will advance basic knowledge about surfactant activity and dysfunction, and define new exogenous surfactants with maximal activity, inhibition resistance, and pulmonary delivery for therapeutic applications.